Multicenter performance evaluation and reference range determination of a new one‐stage factor VIII assay

Lowe, Anna; Jones, Robert L.; Kitchen, Steve; Geisen, Ulrich; Rozsnyai, Gergely; Jilma, Petra; Quehenberger, Peter

doi:10.1002/jcla.24294

Cited by 3 publications

(1 citation statement)

References 19 publications

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“…32,33 The median peak FVIII activity in GENEr8-1 at 26 weeks post gene therapy was 66 IU/dL. Given the ULN for FVIII activity is 150 IU/dL, 34 the combined effect of gene therapy-derived FVIII and emicizumab are still well within normal limits for most individuals, even if they are still receiving emicizumab prophylaxis. For the less than 6% of GENEr8-1 participants who reached FVIII activity levels >150 IU/dL by 52 weeks post infusion, 19 none experienced adverse outcomes related to thromboembolic events.…”

Section: Discussionmentioning

confidence: 99%

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A

Agarwal,

Hermans,

Miesbach

et al. 2024

Haemophilia

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IntroductionValoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8‐1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8‐1 enrolment since emicizumab was an investigational therapy at the time of trial initiation.AimUtilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec.MethodsTo estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time‐course data for participants in GENEr8‐1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion.ResultsSimulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8‐1 participants are presented to illustrate how decisions may vary among individuals.ConclusionPharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy‐derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec.

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Section: Discussionmentioning

confidence: 99%

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A

Agarwal,

Hermans,

Miesbach

et al. 2024

Haemophilia

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Multicenter performance evaluation and reference range determination of a new one‐stage factor VIII assay

Lowe¹,

Jones²,

Kitchen³

et al. 2022

Clinical Laboratory Analysis

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Introduction:We conducted a multicenter evaluation of a new one-stage factor VIII (FVIII) assay (Roche Diagnostics), intended for the quantitative assessment of FVIII activity. We evaluated the analytical performance of the FVIII assay on the cobas t 711 analyzer.Methods: Experiments performed at three laboratories used 3.2% citrated residual or commercially purchased plasma samples. Five human plasma pools and two controls were used to determine assay within-run and within-laboratory precision, and total reproducibility; coefficients of variation (CVs) and/or standard deviations (SDs) were calculated. Lot-to-lot variability and method comparison (vs Coagulation FVIII Deficient Plasma/Dade Actin FS Activated PTT reagent/Standard Human Plasma Calibrator on the Sysmex CS-5100 analyzer; Siemens Healthineers) were evaluated by Passing-Bablok and Deming regression, respectively, and Pearson's r calculated.Assay-specific reference range was determined using 199 fresh plasma samples from healthy adults, not receiving anticoagulants.Results: Across sites, SDs for repeatability were 0.016-0.046 for samples with ≤1.0 international units (IU)/dL FVIII activity; CVs were 0.9%-3.8% for samples with >1.0 IU/dl activity. Among samples with mean FVIII activity 0.344-133 IU/dl, good intermediate precision (SD 0.020 for samples with 0.344 IU/dl activity; CV 1.8%-4.7%) and good total reproducibility (CV 2.0%-13.3%) were observed. The FVIII assay showed excellent lot-to-lot variability (Pearson's r = .999) and good correlation with the comparator assay (Pearson's r = .993-.996). The reference range for FVIII activity was 82.2−218.0 IU/dl. Conclusion:The one-stage FVIII assay demonstrated robust analytical performance on the cobas t 711 analyzer, supporting its use in routine laboratory practice.

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Effect of increasing the number of repeated measurements on the accuracy of determining factor VIII activity and fibrinogen concentrations in blood plasma

Lemondzhava,

Sidorkevich,

Kasyanov

2024

Gematologiâ i transfuziologiâ

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Introduction. Highly accurate determination of hemostatic indices of plasma and blood plasma products is important for industrial transfusiology and monitoring the effi cacy of their clinical application. Repeated measurements increase statistical power, thereby reducing the likelihood of committing a second-order error, which is described as a false negative result and occurs when a test fails to detect a truly existing effect. Aim: to evaluate the effect of increasing the number of repeated measurements on the accuracy of factor VIII activity and fi brinogen concentrations in donor plasma. Materials and methods. Human donor plasma used in the study was obtained by centrifugation of whole blood. The criterion for inclusion of biomaterial in the study was the presence of a non-repeatable combination of donor characteristics: sex, age, blood group and Rhesus affi liation by the presence of D antigen. Whole blood donors for this work were male and female aged between 38 and 53 years with groups: O(I), A(II) and B(III). 27 repeated measurements of factor VIII activity by the one-stage clotting method and fi brinogen concentrations by the Clauss clotting method were performed on automatic coagulometer ACL TOP 300 with HemosIL reagents. Results. For factor VIII activity, the difference in values recorded in repeated measurements reached 20 IU/100 ml, and for fi brinogen concentrations the maximum difference was 0.29 g/L. The calculation of the change in the size of the confi dence interval with increasing number of repeated measurements is presented. While the decrease in size from the second to the fourth repeated measurement averaged 83.5 % for the measurement of factor VIII activity and 61.7 % for fi brinogen concentrations, from the fi fth to the seventh it was 16.9 % and 21.5 %, respectively. Conclusions. Despite the pre-analytical measures taken to reduce random error, blood plasma parameters of the same donation can take values in a wide range. Increasing the number of repeat measurements from one to three in the case of measuring factor VIII activity and fi brinogen concentrations is an effective means of improving the accuracy of these indices. However, with subsequent repeated measurements there will be a decrease in statistical power growth.

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Multicenter performance evaluation and reference range determination of a new one‐stage factor VIII assay

Cited by 3 publications

References 19 publications

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A

Transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy: A simulation study for individuals with severe haemophilia A

Multicenter performance evaluation and reference range determination of a new one‐stage factor VIII assay

Effect of increasing the number of repeated measurements on the accuracy of determining factor VIII activity and fibrinogen concentrations in blood plasma

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